新型钒氧配合物对糖尿病小鼠肾脏功能及胰岛素受体信号转导的影响
|
摘要
糖尿病是一种常见的代谢类疾病,近年来,发病率逐步升高,其临床表现主要有血糖升高、胰岛素抵抗以及糖尿病引起的各种并发症,如高血压、神经病变、增生性视网膜病和肾病综合症等,其中糖尿病肾病综合症(diabeticnephropathy,DN)是常见的微血管并发症,严重威胁糖尿病患者的生命及生活质量。DN的确切发病机制不明,目前认为受多方面因素的影响,包括代谢因素、血流动力学因素、氧化应激和遗传因素等,因此研究DN的发病机制对糖尿病。肾病的治疗具有重要意义。钒是人体必需的微量元素之一。研究表明,无机钒化合物和有机钒化合物均可改善糖尿病大鼠的高血糖症状,促进葡萄糖转运和糖原合成。但无机钒化合物的胃肠道吸收率低,服用高剂量化合物后,实验动物常出现腹泻、精神萎靡、死亡等现象。与无机钒化合物相比,有机钒化合物能提高钒在体内吸收率及生物利用率,并且有机钒氧配合物的降糖效果更为明显,毒副作用也较低,其作用机制并不完全清楚。
本论文采用实验室前期筛选出来的低毒有机钒氧配合物NVC-T2对四氧嘧啶诱导的糖尿病小鼠进行给药干预,检测有机钒氧配合物干预后各组小鼠血糖、血清肌酐、血尿素氮、谷丙转氨酶和谷草转氨酶等的变化,评价其对糖尿病小鼠肾功能的影响。蛋白质免疫印迹检测NVC-T2给药干预后糖尿病小鼠。肾皮层及不同浓度葡萄糖刺激的肾小球系膜细胞中胰岛素受体信号转导通路相关蛋白的表达,进一步探讨NVC-T2类胰岛素作用的信号转导机制,旨在为有机钒化合物成为糖尿病肾病治疗药物的研发提供一定的理论基础。实验结果:
(1)有机钒氧配合物NVC-T2给药干预后,糖尿病组小鼠血糖、血清肌酐、血尿素氮含量明显下降,谷丙转氨酶和谷草转氨酶的比值升高。同时,通过制作组织切片观察糖尿病小鼠肾小球,发现糖尿病小鼠肾小球发生了明显的形态学变化。
(2)与对照组小鼠相比,糖尿病小鼠肾皮层中Cav-1、MAPK和p-MAPK表达量均上调,经NVC-T2给药干预后下调。糖尿病小鼠肾皮层中p-Akt蛋白表达量下调,NVC-T2给药干预后上调。总Akt表达量和对照组小鼠基本一致。
(3)与低糖对照组肾小球系膜细胞相比,高糖刺激的肾小球系膜细胞中Cav-1、MAPK和p-MAPK蛋白表达量显著上调,p-Akt蛋白表达量显著下调。Akt蛋白表达量上调,但与对照组相比,无显著性差异。NVC-T2刺激后,Cav-1、MAPK、p-MAPK和Akt表达量均下调,p-Akt蛋白表达量上调。
结论:1.有机钒氧配合物NVC-T2具有明显的降血糖效果,可以改善糖尿病小鼠的肝肾功能。
2.NVC-T2可明显上调糖尿病小鼠肾皮层和高糖刺激的肾小球系膜细胞中p-Akt蛋白的表达,下调MAPK蛋白和p-MAPK蛋白的表达,提示其对糖尿病小鼠肾功能的影响可能与胰岛素受体起始的PI3K/Akt通路及Ras/MAPK通路有关。
3.糖尿病小鼠肾皮层及高糖刺激的肾小球系膜细胞中Cav-1蛋白的表达量升高,Ras/MAPK通路被激活,而PI3K/Akt通路被抑制,提示在糖尿病肾病的发展过程中Cav-1蛋白可能是通过调节胰岛素信号受体信号转到而起重要的作用。
Diabetes is a common metabolic disease, recently, the incidence of diabetes was escalate in China, the clinical manifestations of diabetes were shown as hyperglycemia, insulin resistance and complications induced by diabetes, such as hypertension, neuropathy, proliferative retinopathy and diabetic nephropathy, DN. DN is a kind of microvascular complications which seriously affect the quality of life of diabetic patients. The pathogenesis of DN is unclear. It is considered that multiple factors can induced DN include metabolic factors, hemodynamic factors, oxidative stress and genetic factors. So there is important significance to research the pathogenesis of DN for the treatment of DN.
Vanadium is one of necessary trace elements for human body. The results show that both inorganic vanadium complexes and organic vanadium complexes can increase glucose level of diabetic rats, promote glucose transport and glycogen synthesis. But the absorption rate of gastrointestinal tract of inorganic vanadium complexes is lower than organic vanadium complexes. Inorganic vanadium complexes often result in diarrhea and death of experimental animals. Organic vanadium complexes can improve the absorption rate and bioavailability of vanadium, and its hypoglycemic effect is more significant, they have low toxicity. But its mechanism is still unclear.
In this study, we use the organic vanadium complex NVC-T2 selected with low toxicity to intervene the diabetic mice induced by alloxan, detect the change of glucose level, serum Cr, BUN, AST and ALT, evaluate its effect on the renal function of diabetic mice. Western blot detects the expression of associated proteins of insulin receptor signal transduction pathway in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose, investigate the signal transduction mechanism of insulin like activity of NVC-T2. Our results showed that:
(1) After the intervention of NVC-T2, the glucose level, serum Cr and BUN of diabetic mice decreased, AST/ALT rates increased. Observe the glomerular by histological sections, we found that the glomerular of diabetic mice occurred significant histopathologic changes.
(2) Compared with control mice, the expression of Cav-1, MAPK, p-MAPK, increased significantly in the renal cortex of diabetic mice. After the intervention of NVC-T2, their expression decreased. The expression of p-Akt decreased, after the intervention of NVC-T2, its expression increased. The expression of Akt was similar with control mice.
(3) Compared with control glomerular mesangial cells, the expression of Cav-1, MAPK, p-MAPK, increased significantly in glomerular mesangial cells stimulated by high glucose. The expression of p-Akt decreased significantly. The expression of Akt increased, but there was no significant difference compared with control glomerular mesangial cells. After the stimulation of NVC-T2, the expression of Cav-1, MAPK, p-MAPK, decreased, p-Akt increased.
Conclusion:
1. Organic vanadium complex NVC-T2 has obvious hypoglycemic effect and can improve hepatic and renal function.
2. After the intervention of NVC-T2, the expression of p-Akt increased, the expression of MAPK, p-MAPK, decreased in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose. Indicate that the effect of NVC-T2 on the renal function of diabetic mice may have relationship with PI3K/Akt pathway and Ras/MAPK pathway.
3. The expression of Cav-1 increased in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose. Ras/MAPK pathway was activated ,and PI3K/Akt pathway was inhibited, indicate that Cav-1 may play an importmant rolein the development of DN by regulating insulin receptor signal transduction pathway
本论文采用实验室前期筛选出来的低毒有机钒氧配合物NVC-T2对四氧嘧啶诱导的糖尿病小鼠进行给药干预,检测有机钒氧配合物干预后各组小鼠血糖、血清肌酐、血尿素氮、谷丙转氨酶和谷草转氨酶等的变化,评价其对糖尿病小鼠肾功能的影响。蛋白质免疫印迹检测NVC-T2给药干预后糖尿病小鼠。肾皮层及不同浓度葡萄糖刺激的肾小球系膜细胞中胰岛素受体信号转导通路相关蛋白的表达,进一步探讨NVC-T2类胰岛素作用的信号转导机制,旨在为有机钒化合物成为糖尿病肾病治疗药物的研发提供一定的理论基础。实验结果:
(1)有机钒氧配合物NVC-T2给药干预后,糖尿病组小鼠血糖、血清肌酐、血尿素氮含量明显下降,谷丙转氨酶和谷草转氨酶的比值升高。同时,通过制作组织切片观察糖尿病小鼠肾小球,发现糖尿病小鼠肾小球发生了明显的形态学变化。
(2)与对照组小鼠相比,糖尿病小鼠肾皮层中Cav-1、MAPK和p-MAPK表达量均上调,经NVC-T2给药干预后下调。糖尿病小鼠肾皮层中p-Akt蛋白表达量下调,NVC-T2给药干预后上调。总Akt表达量和对照组小鼠基本一致。
(3)与低糖对照组肾小球系膜细胞相比,高糖刺激的肾小球系膜细胞中Cav-1、MAPK和p-MAPK蛋白表达量显著上调,p-Akt蛋白表达量显著下调。Akt蛋白表达量上调,但与对照组相比,无显著性差异。NVC-T2刺激后,Cav-1、MAPK、p-MAPK和Akt表达量均下调,p-Akt蛋白表达量上调。
结论:1.有机钒氧配合物NVC-T2具有明显的降血糖效果,可以改善糖尿病小鼠的肝肾功能。
2.NVC-T2可明显上调糖尿病小鼠肾皮层和高糖刺激的肾小球系膜细胞中p-Akt蛋白的表达,下调MAPK蛋白和p-MAPK蛋白的表达,提示其对糖尿病小鼠肾功能的影响可能与胰岛素受体起始的PI3K/Akt通路及Ras/MAPK通路有关。
3.糖尿病小鼠肾皮层及高糖刺激的肾小球系膜细胞中Cav-1蛋白的表达量升高,Ras/MAPK通路被激活,而PI3K/Akt通路被抑制,提示在糖尿病肾病的发展过程中Cav-1蛋白可能是通过调节胰岛素信号受体信号转到而起重要的作用。
Diabetes is a common metabolic disease, recently, the incidence of diabetes was escalate in China, the clinical manifestations of diabetes were shown as hyperglycemia, insulin resistance and complications induced by diabetes, such as hypertension, neuropathy, proliferative retinopathy and diabetic nephropathy, DN. DN is a kind of microvascular complications which seriously affect the quality of life of diabetic patients. The pathogenesis of DN is unclear. It is considered that multiple factors can induced DN include metabolic factors, hemodynamic factors, oxidative stress and genetic factors. So there is important significance to research the pathogenesis of DN for the treatment of DN.
Vanadium is one of necessary trace elements for human body. The results show that both inorganic vanadium complexes and organic vanadium complexes can increase glucose level of diabetic rats, promote glucose transport and glycogen synthesis. But the absorption rate of gastrointestinal tract of inorganic vanadium complexes is lower than organic vanadium complexes. Inorganic vanadium complexes often result in diarrhea and death of experimental animals. Organic vanadium complexes can improve the absorption rate and bioavailability of vanadium, and its hypoglycemic effect is more significant, they have low toxicity. But its mechanism is still unclear.
In this study, we use the organic vanadium complex NVC-T2 selected with low toxicity to intervene the diabetic mice induced by alloxan, detect the change of glucose level, serum Cr, BUN, AST and ALT, evaluate its effect on the renal function of diabetic mice. Western blot detects the expression of associated proteins of insulin receptor signal transduction pathway in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose, investigate the signal transduction mechanism of insulin like activity of NVC-T2. Our results showed that:
(1) After the intervention of NVC-T2, the glucose level, serum Cr and BUN of diabetic mice decreased, AST/ALT rates increased. Observe the glomerular by histological sections, we found that the glomerular of diabetic mice occurred significant histopathologic changes.
(2) Compared with control mice, the expression of Cav-1, MAPK, p-MAPK, increased significantly in the renal cortex of diabetic mice. After the intervention of NVC-T2, their expression decreased. The expression of p-Akt decreased, after the intervention of NVC-T2, its expression increased. The expression of Akt was similar with control mice.
(3) Compared with control glomerular mesangial cells, the expression of Cav-1, MAPK, p-MAPK, increased significantly in glomerular mesangial cells stimulated by high glucose. The expression of p-Akt decreased significantly. The expression of Akt increased, but there was no significant difference compared with control glomerular mesangial cells. After the stimulation of NVC-T2, the expression of Cav-1, MAPK, p-MAPK, decreased, p-Akt increased.
Conclusion:
1. Organic vanadium complex NVC-T2 has obvious hypoglycemic effect and can improve hepatic and renal function.
2. After the intervention of NVC-T2, the expression of p-Akt increased, the expression of MAPK, p-MAPK, decreased in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose. Indicate that the effect of NVC-T2 on the renal function of diabetic mice may have relationship with PI3K/Akt pathway and Ras/MAPK pathway.
3. The expression of Cav-1 increased in the renal cortex of diabetic mice and glomerular mesangial cells stimulated by high glucose. Ras/MAPK pathway was activated ,and PI3K/Akt pathway was inhibited, indicate that Cav-1 may play an importmant rolein the development of DN by regulating insulin receptor signal transduction pathway
引文
[1]Dongren Wang.In vitro study of the insulin-mimetic behaviour of vanadium(Ⅳ,Ⅴ)coordination compounds.Biol Inorg Chem,2002,7:384-396.
[2]Okunura N,and Shimaza T.Vanadate Stimulates D-glulose transport into sarcolemmalv esicles from rat skeletal muscles.Bio Chem,1992,112:107-111.
[3]Stout HV,Vicario PP,Biswas C,et al.Vanadate treatment of streptozocin diabetic rats restores expression of the insulin-response glucose transportor in skeletal muscle. Endocrinology, 1990, 126:2728-2732.
[4] Tolman EL, Barris E, Burns M, Pansini A, Partridge R. Effects of vanadium on glucose metabolism in vitro. Life Sci, 1979, 25(13):1159-64.
[5] Tamura S, Brown TA, Dubler RE, Larner J. Insulin-like effect of vanadate on adipocyte glycogen synthase and on phosphorylation of 95,000 dalton subunit of insulin receptor. Biochem Biophys Res Commun, 1983, 113(1) 539-546.
[6] Brichard SM, Bailey CJ, and Henquin JC. Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes, 1990, 39: 1326-1332.
[7] Brichard SM, Ongemba LN, Henquin JC. Oral vanadate decreases muscle insulin resistance in obese fa/fa rats. Diabetologia, 1992, 35:552-527.
[8] Boderr G, Chen X, Ruiz J, et al. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin dependent diabetes mellitus. Metabolism, 1996, 45(8):1130-1135.
[9] Yuen VG, Orvig C and Mcneill JH, et al. Glucose-lowering effects of a new organic vanadium complex, bis(maltolato)oxo-vanadium(IV). Can J Physiol Pharmacol. 1993 Mar-Apr;71(3-4):263-9.
[10] Sakurai H, Fujii K, Watanabe H, et al. Orally active and long-term acting insulin-mimetic vanadyl complex:Bis(picolinato) Oxovanadium(IV). Biochemical and Biophysical research communications, 1995, 214(3):1095-1101.
[11] Faure R, Baquiran G, Bergeron J JM, et al. The dephosphorylation of insulin and epidermal growth factor receptors. Biol Chem, 1992, 267:11215-11221.
[12] Posner BI, Faure R, Burgess JW, et al. Peroxovanadium compounds: a new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. Biol Chem, 1994, 269:4596-4604.
[13] Yale JF, Lachance D, Bevan A, et al. Hypoglycemic effects of Peroxovanadium compounds Sprague-Dawley and Diabetic BB rats. Diabetes, 1995, 44:1274-1279.
[14] H. Sakurai, A. Katoh and Y. Yoshikawa. Chemistry and Biochemistry of Insulin- Mimetic Vanadium and Zinc Complexes. Trial for Treatment of Diabetes Mellitus. Bulletin of the Chemical Society of Japan, 2006, 79, 1645 -1664.
[15] Li M, Smee JJ, Ding W, Crans DC. Anti-diabetic effects ofsodium4-amino-2, 6- dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats. Inorg Biochem, 2008, 69:331-339.
[16] 李杰,邵明柏,孔俭. 硫酸氧钒对糖尿病大鼠血糖和血脂的影响[J]. 南京医科学学报(自然科学版), 2003, 23(1): 48-50.
[17] Pugazhenthi S, Hussain A, Yu-B, et al. Vanadate induces norma lipidemia and are duction in the levels of hepatic lipogenic enzymesim obese zucker rat. Mol Cell Biochem, 1995, 1530(2):211-215.
[18] Goldfine AB, Simonson DC, FollF, et al. Metabolic effects of sodium metavanadate in humans with insulin-dependent and non insulin-dependent diaetes mellitus in vivo and in vitro studies. Clin Endocrinol Metab, 1995, 80:3311-3320.
[19] Takeshita S, Kawamura I, Yasuno T, et al. Amelioration of insulin resistance in diabetic ob/ob mice by a new type of orally active insulin-mimetic vanadyl complex: bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) with VO(S(2)O(2)) coordination mode. Inorg Biochem, 2001, 85(2-3):179-186.
[20] Mehdi MZ, Pandey SK, Theberge JF, et al. Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium. Cell Biochem Biophys, 2006, 44 (1):73-81.
[21] Fantus IG, Tsiani E. Multifunctional actions of vanadium compounds on insulin signaling pathways: evidence for preferential enhancement of metabolic versus mitogenic effects. Mol Cell Biochem, 1998, 182(1-2):109-119.
[22] Zuo YQ, Liu WP, Niu YF, et al. Bis(alpha-Furancarboxylato) oxovanadium(IV) prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes. Pharm Pharmacol, 2008, 60(10):1335-1340.
[23] Qu H, Yan L, Mustafi D, et al. The vanadyl (VO2+) chelate bis(acetylacetonato) oxovanadium(IV) potentiates tyrosine phosphorylation of the insulin receptor. Biol Inorg Chem, 2005, 10(8):874-886.
[24] Green A. The insulin-like effect of sodium vanadate on adipocyte glucose transport is mediated at a post-insulin-receptor level. Biochem, 1986, 238:663-669.
[25] Bsuki W, Hiromura M, Adachi Y, et al. Enhancement of insulin signaling pathway in adipocytes by oxovanadium(IV) complexes. Biochem biophys res commun, 2006, 349 (3):1163-1170.
[26] M. Hiromura, A. Nakayama, Y. Adachi, et al. Action mechanism of bis(allixinato) oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor. Biol Inorg Chem, 2007, 12, 1275.
[27] Shisheva A, Shechter Y. Role of cytosolic tyrosine kinase in mediating insulin-like actions of vanadate in rat adipocytes. Biol Chem, 1993, 268(9):6463-6469.
[28] Yamazaki RK, Hirabara SM, Tchaikovski OJ, et al. The effects of peroxovanadate and peroxovanadyl on glucose metabolism in vivo and identification of signal transduction proteins involved in the mechanism of action in isolated soleus muscle. Mol Cell Biochemk, 2005, 273(1-2):145-150.
[29]Hei YJ, Farahbakhshian S, Chen X, et al. Stimulation of MAP kinase and S6 kinase by vanadium and selenium in rat adipocytes. Molecular and cellular biochemistry. 1998, 178(1-2): 367-375.
[30] Brownsey RW, Dong GW. Evidence for selective efects of vanadium on adipose cell metabolism involving actions on cAMP-dependent protein kinase. Mol Cell Biochem, 1995, (153):131-137.
[31] Etcheverry SB, Barrio DA, Williams PA, et al. On the interaction of the vanadyl(IV) cation with lactose: inhibition effects of vanadyl(IV)/monosaccharide and disaccharide complexes upon alkaline phosphatase activity. Biol Trace Elem Res, 2001, 84(1-3):227-38.
[32] Morita A, Zhu J, Suzuki N, et al. Sodium orthovanadate suppresses DNA damage- induced caspase activation and apoptosis by inactivating p53. Cell Death Differ, 2006, 13(3):499-511.
[1]Heyliger CE,McNeill JH.Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats.Science,1985,227:1474-1477.
[2]Ramanadham D,Mongold J,McNeill JH.Oral vanadily sulfate in treatment of diabetic mellitus in rats.Am J Physiol,1989,257:904-911.
[3]Sakurai H.A new concept:the use of vanadium complexes in the treatment of diabetic mellitus.Chem Rec,2002,2(4):237-248.
[4]李杰,邵明柏,孔俭.硫酸氧钒对糖尿病大鼠血糖和血脂的影响.南京医科大学学报,2003,23(1):48-50.
[5]孙杰,孔俭.糖尿病大鼠心肌GluT4mRNA的表达水平.中国老年学杂志.2000,20(3):170-171.
[6]金文胜,张忠辉,张平.正钒酸钠对大鼠骨骼肌体外葡萄糖摄取的影响及其与cAMP的关系.中华内分泌代谢杂志,2000,16(2):126-127.
[7]Li SH,McNeill JH.In vivo effects of vanadium on GLUT4 translocation in cardiac tissue of STZ-diabetic rats.Molcell biochem,2001,217(1-2):121-129.
[8]Dongren Wang.In vitro study of the insulin-mimetic behaviour of vanadium(Ⅳ,Ⅴ)coordination compounds.Biol Inorg Chem,2002,7:384-396.
[9]徐明智,张爱珍.钒的降血糖作用及机制.浙江预防医学,2002,14(7):62-63.
[10]Ann J.Cynthia J.Burrows.Guanine versus deoxyribose damage in DNA oxidation mediated by vanadium(Ⅳ) and vanadium(Ⅴ) complexes[J].Biol Inorg Chem,2001,6:100-106.
[11]张均田.现代药理实验方法.北京医科大学中国协和医科大学联合出版社,1998,981.
[1]Ziyaden FN,Hoffman BB,Han DC,et al.Long-term prevention of renal insufficiency,excess matrix gene expression,and glomerrular mesangial matrix expansion by treatmentwith monoclonal anti-transforming growth factor-beta antibody in db/db diabetic mice.Proc Natl Acad SciUSA,2000,97(14):8015-8020.
[2]Fresno-Vara JA,Casado E,De-Castro J,et al.PI3K/AKT signaling pathway and cancer. Cancer Treat Rev, 2004, 30(2):193-204.
[3] Li Q, Zhu GD. Targeting serine/Threonine protein Kinase B/AKT and cell cycle checkpoint kinase for treating cancer. Curr Top Med Chem, 2002, 2(9):939-971.
[4] RobinsonMJ, CobbMH, Miki Y. Mitogen activated protein kinase pathway. Cell Biol, 1997, 9(2):180-186.
[5] Sakurai H. A new concept:the use of vanadium complexes in the treatment of diabetic mellitus. Chem Rec, 2002, 2(4): 237-248.
[6] Dieter Rehder. In vitro study of the insulin-mimetic behaviour of vanadium (IV, V) coordination compounds. Biol Inorg Chem, 2002, 7:384-396.
[7] Bhuiyan MS, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K. Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther. 2008 Spring;26(1):10-23.
[8] Itzhak Goldwaser, Dov Gefel, Eytan Gershonov, et al. Insulin-like effects of vanadium: basic and clinical implications. Journal of Inorganic Biochemistry, 2000, 80:21-25.
[9] Dieter Rehder. In vitro study of the insulin-mimetic behaviour of vanadium (IV, V) coordination compounds. Biol Inorg Chem. 2002, 7: 384-396.
[10] Mohamad Z. Mehdi, Ashok K. Srivastava. Organo-vanadium compounds are potent activators of the protein kinase B signaling pathway and protein tyrosine phosphorylation: Mechanism of insulinomimesis. Archives of Biochemistry and Biophysics, 2005, 440:158-164.
[11] Zhang W, Li HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cell. Cell Res, 2002, 12(1):9-18.
[12] Palade GE. Fine structure of blood capillaries. J Appl Physiol. 1953, 24:1424- 1436.
[13] Okamoto T, Schlegel A, Scherer PE, et al. Caveolins, a family of scaffolding proteins for organizing" preassembled signaling complexes" at the plasma membrane. J Biol Chem, 1998, 273:5419-5422.
[14] Smart EJ, Graf GA, McNiven MA, et al. Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol, 1999, 19:7289-7304.
[15] Rothberg KG, Heuser JE, Donzell WC, et al. Caveolin, a protein component of caveolae membrane coats. Cell, 1992, 68:673-682.
[16] Schlegel A, Lisanti MP. Caveolae and their coat proteins, the caveolins: from electron microscopic novelty to biological launching pad. J Cell Physiol, 2001, 186:329-337.
[17] Palade GE, Bruns RR. Structural modification of plasmalemma vesicle. J Cell Biol, 1968, 37:633-649.
[18] Yamada E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol, 1955, 1:1078-1085.
[19] Alex W. Cohen, Terry P. Combs, Philip E. Scherer, et al. Role of Caveolin and caveolae in insulin signaling and diabetes. Am J Physiol Endocrinol Metab, 2003, 10.1152, 285: 1151-1160.
[1]Fresno-Vara JA,Casado E,De-Castro J,et al.PI3K/AKT signaling pathway and cancer.Cancer Treat Rev,2004,30(2):193-204.
[2]Zhang X,Shen P,Coleman M,et al.Caveolin-1 downregulation activates estrogen receptor alphaexpression and leads to 17β-estradiol-stimulated mammary tumorigenesis.Anticancer Res,2005,25(A):369-375.
[3]English J,Pearson G,Wilsbacher J,et al.New insights into the control of MAP kinase pathways.Exp Cell Res,1999,253:255-270.
[4]Kennedy N J,Davis R J.Role of JNK in tumor development.Cell Cycle,2003,2(3):199-201.
[5]Sakurai T,Maeda S,Chang L,et al.Loss of hepatic NF-kB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation.Proc Nail Acad Sci USA,2006,103(28):10544-10551.
[6]Lee S A,Jung M.The nucleoside analog sangivamycin induces apoptotic cell death in breast carcinoma MCF7/Adriamycin-resistant cells via protein kinase Cdeha and JNK activation.J Biol Chem,2007,282(20):15271-15283.
[7]Moon D,Kim M O,Kang S H.et al.Induction of G2/Marrest,endoreduplication,and apoptosis by aetin depolymerization agent pextenotoxin-2 in human leukemia cells,involving activation of ERK and JNK.Biochem Pharmacol,2008,76(3):312-321.
[8]Alex W,Cohen,Terry P,Combs,Philip E.Scherer and Michael P.Lisanti.Role of Caveolin and caveolae in insulin signaling and diabetes.Am J Physiol Endocrinol Metab,2003,10,1152(285)1151-1160.
[2]Okunura N,and Shimaza T.Vanadate Stimulates D-glulose transport into sarcolemmalv esicles from rat skeletal muscles.Bio Chem,1992,112:107-111.
[3]Stout HV,Vicario PP,Biswas C,et al.Vanadate treatment of streptozocin diabetic rats restores expression of the insulin-response glucose transportor in skeletal muscle. Endocrinology, 1990, 126:2728-2732.
[4] Tolman EL, Barris E, Burns M, Pansini A, Partridge R. Effects of vanadium on glucose metabolism in vitro. Life Sci, 1979, 25(13):1159-64.
[5] Tamura S, Brown TA, Dubler RE, Larner J. Insulin-like effect of vanadate on adipocyte glycogen synthase and on phosphorylation of 95,000 dalton subunit of insulin receptor. Biochem Biophys Res Commun, 1983, 113(1) 539-546.
[6] Brichard SM, Bailey CJ, and Henquin JC. Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes, 1990, 39: 1326-1332.
[7] Brichard SM, Ongemba LN, Henquin JC. Oral vanadate decreases muscle insulin resistance in obese fa/fa rats. Diabetologia, 1992, 35:552-527.
[8] Boderr G, Chen X, Ruiz J, et al. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin dependent diabetes mellitus. Metabolism, 1996, 45(8):1130-1135.
[9] Yuen VG, Orvig C and Mcneill JH, et al. Glucose-lowering effects of a new organic vanadium complex, bis(maltolato)oxo-vanadium(IV). Can J Physiol Pharmacol. 1993 Mar-Apr;71(3-4):263-9.
[10] Sakurai H, Fujii K, Watanabe H, et al. Orally active and long-term acting insulin-mimetic vanadyl complex:Bis(picolinato) Oxovanadium(IV). Biochemical and Biophysical research communications, 1995, 214(3):1095-1101.
[11] Faure R, Baquiran G, Bergeron J JM, et al. The dephosphorylation of insulin and epidermal growth factor receptors. Biol Chem, 1992, 267:11215-11221.
[12] Posner BI, Faure R, Burgess JW, et al. Peroxovanadium compounds: a new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. Biol Chem, 1994, 269:4596-4604.
[13] Yale JF, Lachance D, Bevan A, et al. Hypoglycemic effects of Peroxovanadium compounds Sprague-Dawley and Diabetic BB rats. Diabetes, 1995, 44:1274-1279.
[14] H. Sakurai, A. Katoh and Y. Yoshikawa. Chemistry and Biochemistry of Insulin- Mimetic Vanadium and Zinc Complexes. Trial for Treatment of Diabetes Mellitus. Bulletin of the Chemical Society of Japan, 2006, 79, 1645 -1664.
[15] Li M, Smee JJ, Ding W, Crans DC. Anti-diabetic effects ofsodium4-amino-2, 6- dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats. Inorg Biochem, 2008, 69:331-339.
[16] 李杰,邵明柏,孔俭. 硫酸氧钒对糖尿病大鼠血糖和血脂的影响[J]. 南京医科学学报(自然科学版), 2003, 23(1): 48-50.
[17] Pugazhenthi S, Hussain A, Yu-B, et al. Vanadate induces norma lipidemia and are duction in the levels of hepatic lipogenic enzymesim obese zucker rat. Mol Cell Biochem, 1995, 1530(2):211-215.
[18] Goldfine AB, Simonson DC, FollF, et al. Metabolic effects of sodium metavanadate in humans with insulin-dependent and non insulin-dependent diaetes mellitus in vivo and in vitro studies. Clin Endocrinol Metab, 1995, 80:3311-3320.
[19] Takeshita S, Kawamura I, Yasuno T, et al. Amelioration of insulin resistance in diabetic ob/ob mice by a new type of orally active insulin-mimetic vanadyl complex: bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) with VO(S(2)O(2)) coordination mode. Inorg Biochem, 2001, 85(2-3):179-186.
[20] Mehdi MZ, Pandey SK, Theberge JF, et al. Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium. Cell Biochem Biophys, 2006, 44 (1):73-81.
[21] Fantus IG, Tsiani E. Multifunctional actions of vanadium compounds on insulin signaling pathways: evidence for preferential enhancement of metabolic versus mitogenic effects. Mol Cell Biochem, 1998, 182(1-2):109-119.
[22] Zuo YQ, Liu WP, Niu YF, et al. Bis(alpha-Furancarboxylato) oxovanadium(IV) prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes. Pharm Pharmacol, 2008, 60(10):1335-1340.
[23] Qu H, Yan L, Mustafi D, et al. The vanadyl (VO2+) chelate bis(acetylacetonato) oxovanadium(IV) potentiates tyrosine phosphorylation of the insulin receptor. Biol Inorg Chem, 2005, 10(8):874-886.
[24] Green A. The insulin-like effect of sodium vanadate on adipocyte glucose transport is mediated at a post-insulin-receptor level. Biochem, 1986, 238:663-669.
[25] Bsuki W, Hiromura M, Adachi Y, et al. Enhancement of insulin signaling pathway in adipocytes by oxovanadium(IV) complexes. Biochem biophys res commun, 2006, 349 (3):1163-1170.
[26] M. Hiromura, A. Nakayama, Y. Adachi, et al. Action mechanism of bis(allixinato) oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor. Biol Inorg Chem, 2007, 12, 1275.
[27] Shisheva A, Shechter Y. Role of cytosolic tyrosine kinase in mediating insulin-like actions of vanadate in rat adipocytes. Biol Chem, 1993, 268(9):6463-6469.
[28] Yamazaki RK, Hirabara SM, Tchaikovski OJ, et al. The effects of peroxovanadate and peroxovanadyl on glucose metabolism in vivo and identification of signal transduction proteins involved in the mechanism of action in isolated soleus muscle. Mol Cell Biochemk, 2005, 273(1-2):145-150.
[29]Hei YJ, Farahbakhshian S, Chen X, et al. Stimulation of MAP kinase and S6 kinase by vanadium and selenium in rat adipocytes. Molecular and cellular biochemistry. 1998, 178(1-2): 367-375.
[30] Brownsey RW, Dong GW. Evidence for selective efects of vanadium on adipose cell metabolism involving actions on cAMP-dependent protein kinase. Mol Cell Biochem, 1995, (153):131-137.
[31] Etcheverry SB, Barrio DA, Williams PA, et al. On the interaction of the vanadyl(IV) cation with lactose: inhibition effects of vanadyl(IV)/monosaccharide and disaccharide complexes upon alkaline phosphatase activity. Biol Trace Elem Res, 2001, 84(1-3):227-38.
[32] Morita A, Zhu J, Suzuki N, et al. Sodium orthovanadate suppresses DNA damage- induced caspase activation and apoptosis by inactivating p53. Cell Death Differ, 2006, 13(3):499-511.
[1]Heyliger CE,McNeill JH.Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats.Science,1985,227:1474-1477.
[2]Ramanadham D,Mongold J,McNeill JH.Oral vanadily sulfate in treatment of diabetic mellitus in rats.Am J Physiol,1989,257:904-911.
[3]Sakurai H.A new concept:the use of vanadium complexes in the treatment of diabetic mellitus.Chem Rec,2002,2(4):237-248.
[4]李杰,邵明柏,孔俭.硫酸氧钒对糖尿病大鼠血糖和血脂的影响.南京医科大学学报,2003,23(1):48-50.
[5]孙杰,孔俭.糖尿病大鼠心肌GluT4mRNA的表达水平.中国老年学杂志.2000,20(3):170-171.
[6]金文胜,张忠辉,张平.正钒酸钠对大鼠骨骼肌体外葡萄糖摄取的影响及其与cAMP的关系.中华内分泌代谢杂志,2000,16(2):126-127.
[7]Li SH,McNeill JH.In vivo effects of vanadium on GLUT4 translocation in cardiac tissue of STZ-diabetic rats.Molcell biochem,2001,217(1-2):121-129.
[8]Dongren Wang.In vitro study of the insulin-mimetic behaviour of vanadium(Ⅳ,Ⅴ)coordination compounds.Biol Inorg Chem,2002,7:384-396.
[9]徐明智,张爱珍.钒的降血糖作用及机制.浙江预防医学,2002,14(7):62-63.
[10]Ann J.Cynthia J.Burrows.Guanine versus deoxyribose damage in DNA oxidation mediated by vanadium(Ⅳ) and vanadium(Ⅴ) complexes[J].Biol Inorg Chem,2001,6:100-106.
[11]张均田.现代药理实验方法.北京医科大学中国协和医科大学联合出版社,1998,981.
[1]Ziyaden FN,Hoffman BB,Han DC,et al.Long-term prevention of renal insufficiency,excess matrix gene expression,and glomerrular mesangial matrix expansion by treatmentwith monoclonal anti-transforming growth factor-beta antibody in db/db diabetic mice.Proc Natl Acad SciUSA,2000,97(14):8015-8020.
[2]Fresno-Vara JA,Casado E,De-Castro J,et al.PI3K/AKT signaling pathway and cancer. Cancer Treat Rev, 2004, 30(2):193-204.
[3] Li Q, Zhu GD. Targeting serine/Threonine protein Kinase B/AKT and cell cycle checkpoint kinase for treating cancer. Curr Top Med Chem, 2002, 2(9):939-971.
[4] RobinsonMJ, CobbMH, Miki Y. Mitogen activated protein kinase pathway. Cell Biol, 1997, 9(2):180-186.
[5] Sakurai H. A new concept:the use of vanadium complexes in the treatment of diabetic mellitus. Chem Rec, 2002, 2(4): 237-248.
[6] Dieter Rehder. In vitro study of the insulin-mimetic behaviour of vanadium (IV, V) coordination compounds. Biol Inorg Chem, 2002, 7:384-396.
[7] Bhuiyan MS, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K. Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther. 2008 Spring;26(1):10-23.
[8] Itzhak Goldwaser, Dov Gefel, Eytan Gershonov, et al. Insulin-like effects of vanadium: basic and clinical implications. Journal of Inorganic Biochemistry, 2000, 80:21-25.
[9] Dieter Rehder. In vitro study of the insulin-mimetic behaviour of vanadium (IV, V) coordination compounds. Biol Inorg Chem. 2002, 7: 384-396.
[10] Mohamad Z. Mehdi, Ashok K. Srivastava. Organo-vanadium compounds are potent activators of the protein kinase B signaling pathway and protein tyrosine phosphorylation: Mechanism of insulinomimesis. Archives of Biochemistry and Biophysics, 2005, 440:158-164.
[11] Zhang W, Li HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cell. Cell Res, 2002, 12(1):9-18.
[12] Palade GE. Fine structure of blood capillaries. J Appl Physiol. 1953, 24:1424- 1436.
[13] Okamoto T, Schlegel A, Scherer PE, et al. Caveolins, a family of scaffolding proteins for organizing" preassembled signaling complexes" at the plasma membrane. J Biol Chem, 1998, 273:5419-5422.
[14] Smart EJ, Graf GA, McNiven MA, et al. Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol, 1999, 19:7289-7304.
[15] Rothberg KG, Heuser JE, Donzell WC, et al. Caveolin, a protein component of caveolae membrane coats. Cell, 1992, 68:673-682.
[16] Schlegel A, Lisanti MP. Caveolae and their coat proteins, the caveolins: from electron microscopic novelty to biological launching pad. J Cell Physiol, 2001, 186:329-337.
[17] Palade GE, Bruns RR. Structural modification of plasmalemma vesicle. J Cell Biol, 1968, 37:633-649.
[18] Yamada E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol, 1955, 1:1078-1085.
[19] Alex W. Cohen, Terry P. Combs, Philip E. Scherer, et al. Role of Caveolin and caveolae in insulin signaling and diabetes. Am J Physiol Endocrinol Metab, 2003, 10.1152, 285: 1151-1160.
[1]Fresno-Vara JA,Casado E,De-Castro J,et al.PI3K/AKT signaling pathway and cancer.Cancer Treat Rev,2004,30(2):193-204.
[2]Zhang X,Shen P,Coleman M,et al.Caveolin-1 downregulation activates estrogen receptor alphaexpression and leads to 17β-estradiol-stimulated mammary tumorigenesis.Anticancer Res,2005,25(A):369-375.
[3]English J,Pearson G,Wilsbacher J,et al.New insights into the control of MAP kinase pathways.Exp Cell Res,1999,253:255-270.
[4]Kennedy N J,Davis R J.Role of JNK in tumor development.Cell Cycle,2003,2(3):199-201.
[5]Sakurai T,Maeda S,Chang L,et al.Loss of hepatic NF-kB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation.Proc Nail Acad Sci USA,2006,103(28):10544-10551.
[6]Lee S A,Jung M.The nucleoside analog sangivamycin induces apoptotic cell death in breast carcinoma MCF7/Adriamycin-resistant cells via protein kinase Cdeha and JNK activation.J Biol Chem,2007,282(20):15271-15283.
[7]Moon D,Kim M O,Kang S H.et al.Induction of G2/Marrest,endoreduplication,and apoptosis by aetin depolymerization agent pextenotoxin-2 in human leukemia cells,involving activation of ERK and JNK.Biochem Pharmacol,2008,76(3):312-321.
[8]Alex W,Cohen,Terry P,Combs,Philip E.Scherer and Michael P.Lisanti.Role of Caveolin and caveolae in insulin signaling and diabetes.Am J Physiol Endocrinol Metab,2003,10,1152(285)1151-1160.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |